This invention relates to the synthesis of heteroarylamine compounds which are useful in the production of heteroaryl ureas a key component in pharmaceutically active compounds possessing a heteroaryl urea group.
Aryl- and heteroaryl-substituted ureas have been described as inhibitors of cytokine production. These inhibitors are described as effective therapeutics in cytokine-mediated diseases, including inflammatory and autoimmune diseases. Examples of such compounds are reported in WO 99/23091 and in WO 98/52558.
A key step in the synthesis of these compounds is the formation of the urea bond. Various methods have been reported to accomplish this. For example, as reported in the above references, an aromatic or heteroaromatic amine, Ar1NH2, may be reacted with an aromatic or heteroaromatic isocyanate, Ar2NCO, to generate the urea Ar1HC(O)NHAr2. 
If not commercially available, one may prepare the isocyanate by reaction of an aryl or heteroaryl amine Ar2xe2x80x94NH2 with phosgene or a phosgene equivalent, such as bis(trichloromethyl) carbonate (triphosgene) (P. Majer and R. S. Randad, J. Org. Chem. 1994, 59, 1937) or trichloromethyl chloroformate (diphosgene) (K. Kurita, T. Matsumura and Y. Iwakura, J. Org. Chem. 1976, 41, 2070) to form the isocyanate Ar2xe2x80x94NCO, followed by reaction with Ar1NH2 to provide the urea. Other approaches to forming the urea reported in the chemical literature include reaction of a carbamate with an aryl or heteroaryl amine, (see for example B. Thavonekham, Synthesis, 1997, 1189 and T. Patonay et al., Synthetic Communications, 1996, 26, 4253) as shown in Scheme II. U.S. Provisional Application No. 60/143,094 also discloses a process of making heteroaryl ureas by reacting particular carbamate intermediates with the desired arylamine. 
U.S. application Ser. No. 09/505,582 and PCT/US00/03865 describe cytokine inhibiting ureas of the following formula: 
An intermediate required to prepare preferred compounds described therein has a 1,4-disubstituted naphthalene as Ar2 and is illustrated in the formula below. 
The preparation of these intermediates require the coupling of the naphthyl ring with X. Preferred X include aryl and heteroaryl groups. Previously described methods, including U.S. application Ser. No. 09/505,582 and PCT/US00/03865 achieve the coupling of these aromatic residues by using a coupling reaction catalyzed by a transition metal, such as palladium, in the presence of a ligand, such as triphenyl phosphine. Coupling methods include Stille coupling, requiring the preparation of a tributylstannyl intermediate, or a Suzuki coupling, requiring the preparation of a boronic acid intermediate (Scheme III). 
Some steps in these methods require cooling to extreme temperatures (xe2x88x9278xc2x0 C.). Others require reaction under high pressure, require chromatography to purify the product, or use expensive reagents. For these reasons, these methods are not suitable for large-scale or industrial-scale production.
It is an object of the invention to provide a novel method of producing heteroaryl amines of the formula(I): 
wherein X, Y and Z are described below, the heteroarylamines are useful in the production of heteroaryl ureas as mentioned above.
Disclosed herein is a novel process for preparing preferred heteroarylamine intermediates including those heteroarylamine intermediates described in U.S. application Ser. No. 09/505,582, and PCT/US00/03865. The processes described herein have several advantages. They use inexpensive starting materials and reagents, the reactions are run at moderate temperatures, there are no high-pressure reactions and chromatography is not required.
The novel feature of the invention is the construction of naphthalene ring, as exemplified in Scheme I below, from the appropriately substituted carboxylic acid 5, which in turn was synthesized beginning from a novel ester of the formula (II) and a diester such as diethyl succinate. Any of the compounds of the formula (II) as described herein can be synthesized from readily available and cost efficient starting materials such as example 1 below.
This invention provides a novel strategy for the synthesis of heteroarylamine compounds of the formula (I): 
wherein:
the naphthyl ring is further optionally substituted by one or more R1 or R2;
X is chosen from
a C5-8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
aryl, furanyl, thienyl, pyrrolyl, pyrazolyl, imidazolyl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, C1-4alkoxy, hydroxy, nitro, nitrile, amino, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is chosen from
a bond and a C1-4 saturated or unsaturated branched or unbranched carbon chain optionally partially or fully halogenated, wherein one or more methylene groups are optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
Z is chosen from
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, pyrazolyl, triazolyl, tetrazolyl, furanyl, thienyl, pyranyl, each being optionally substituted with one to three halogen, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, CN, CONH2, COOH or phenylamino wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkyl or C1-6 alkoxy;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, thiomorpholinyl sulfonyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, cyclohexanonyl, cyclohexanolyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfide, tetramethylene sulfoxidyl or tetramethylene sulfonyl each being optionally substituted with one to three nitrile, C1-6 alkyl, C1-6 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino-C1-3 alkyl, CONH2, phenylamino-C1-3 alkyl or C1-3 alkoxy-C1-3 alkyl;
halogen, C1-4 alkyl, nitrile, amino, hydroxy, C1-6 alkoxy, NH2C(O), mono- or di(C1-3alkyl) aminocarbonyl, mono- or di(C1-3alkyl)amino, secondary or tertiary amine wherein the amino nitrogen is covalently bonded to C1-3 alkyl or C1-5 alkoxyalkyl, pyridinyl-C1-3 alkyl, imidazolyl-C1-3 alkyl, tetrahydrofuranyl-C1-3 alkyl, nitrile-C1-3 alkyl, carboxamide-C1-3 alkyl, phenyl, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino, C1-6 alkyl-S(O)m, or phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy, halogen or mono- or di-(C1-3 alkyl)amino;
C1-6 alkyl-S(O)m, and phenyl-S(O)m, wherein the phenyl ring is optionally substituted with one to two halogen, C1-6 alkoxy, hydroxy or mono- or di-(C1-3 alkyl)amino;
R1 and R2 are independently chosen from:
a C1-6 branched or unbranched alkyl optionally partially or fully halogenated, C1-4 branched or unbranched alkoxy, each being optionally partially or fully halogenated, halogen, C1-3 alkyl-S(O)m optionally partially or fully halogenated and phenylsulfonyl;
and
m is 0, 1 or 2.
The process of the invention in its broadest generic aspect is provided below and exemplified in a non-limiting embodiment shown in Scheme 1:
said process comprising:
a) reacting a Zxe2x80x94Yxe2x80x94Xxe2x80x94COOxe2x80x94Rx ester (II) wherein Rx is C1-5alkyl or aryl with a di-alkyl or diaryl ester (III) in a suitable solvent protic or aprotic, polar or nonpolar, preferably aprotic such as THF, DME, DMSO, ether, dioxane, CH2Cl2, CHCl3, toluene, pyridine or DMF, or suitable alcohols, preferably the solvent is chosen from THF and DMSO, more preferably THF, and a suitable base such as organic or inorganic bases such as NaH, NaNH2, sodium alkoxides such as Na-t-butoxide, Na-ethoxide, NaOH, pyridine, TEA, DBU or BuLi, preferably NaH or Na t-butoxide, and optionally where appropriate as in Example 3, in the presence of an additive such as DMPU and HMPA, preferably DMPU, under the temperature of about 0 to 200xc2x0 C. for a reaction time of about 5 min to 24 h, preferably when using the preferred solvent THF at 60-70xc2x0 C. for about 8 h and isolating the compound intermediate (IV). Examples 1 and 2 are representative methods for preparation of compounds of the formula(II), methods of preparing other compounds of the formula(II) is within the skill in the art. 
b) subjecting the product of step a) to acidic or basic hydrolysis, preferably acidic hydrolysis, and decarboxylation under suitable acid conditions apparent to those skilled in the art, such as conc. H2SO4 in HOAc at a temperature of about 50 to 200xc2x0 C. and for about 5 min to 24 hours, preferably about 100xc2x0 C. for about 7 h; followed by esterification under appropriate conditions with a C1-5alcohol, preferably EtOH; subsequent phenyl nucleophilic addition via for example a phenyl Grignard reagent PhMgBr, phenylLi, phenylZnCl, preferably phenyl Grignard, the phenyl being optionally substituted by R1 and/or R2; reductive cleavage under appropriate conditions such as HCOONH4/Pd/C/EtOH to form a carboxylic acid compound which on treatment with a strong mineral acid such as H2SO4, HCl, MeSO3H, CF3SO3H, PPA or Lewis acid such as SnCl4, AlCl3, BF3xe2x80x94OEt2 and Yb(OTf)2, preferably PPA, optionally in a suitable solvent at RT to 200xc2x0 C., preferably about 110xc2x0 C., to form a product intermediate of the formula(V), and isolating the product: 
c) reacting the product from step b) with HNRyRz or it""s respective salt thereof, to form an enamine or imine, preferably an oxime, compound of the formula(VI) under suitable conditions. 
xe2x80x83wherein Ry is C1-5alkyl or hydrogen, Rz is C1-5alkyl, hydrogen or OH with the proviso that when formula (VI) is an enamine tautomer then Ry and Rz are both C1-5alkyl, or when formula (VI) is an imine tautomer then Rz is OH, C1-5alkyl or hydrogen and Ry is not present: 
xe2x80x83In a preferred but nonlimiting embodiment, forming an oxime by adding NH2OH.HCl (where Ry is H and Rz is OH) in a suitable solvent such as EtOH with a suitable base such as NaOH at about RT for about 1 to 24 h, preferably 18 h;
c) 1) where the product of step c) is an imine, preferably an oxime (Ryxe2x95x90H, Rzxe2x95x90OH), preferably in a one pot reaction acylating and reducing the product of step c) under conditions known in the art, a preferred but non-limiting example is acetylating/reducing conditions, such as treating compound (VI) with acetic anhydride, acetic acid and a suitable reducing agent such as Fe, SnCl2 and Zn, preferably Fe, at about 55xc2x0 C. for about 5 hours; then treating the unsaturated amide product (8) under oxidizing conditions capable of forming the naphthalene ring of the formula(I) above, for example, treating the amide product(8) with an oxidizing reagant such as DDQ, O2, CrO3 and KMnO4, preferably DDQ, in a nonpolar solvent such as methylene chloride, at about 0 to 50xc2x0 C., preferably RT for about 0.5 to 10 h, preferably 5 h; followed by deprotection by methods known in the art to provide the formation of formula (I): 
xe2x80x83or
2) where the product of step c) is an enamine, oxidizing the enamine under suitable oxidizing conditions to form the naphthalene ring, then deprotecting the nitrogen to form the amine of the formula (I). In a non-limiting example, Ry and Rz are benzyl, oxidation to the naphthalene ring may be accomplished as described above, and debenzylation may be accomplished by methods known to those skilled in the art, for example H2/palladium/C.
Compounds of the formula (I) possessing a particularly desired Arxe2x80x94Xxe2x80x94Yxe2x80x94Z combination can be synthesized without undue experimentation by variations apparent to those of ordinary skill in the art in view of the teachings in this specification and the state of the art. More specific examples of possible Xxe2x80x94Yxe2x80x94Z combinations are to be found in PCT application no. PCT/US00/03865 and U.S. application Ser. No. 09/505,582 each of which is incorporated herein by reference in their entirety.
In another embodiment of the invention there is provided a novel process of making compounds of the formula(I) as described above and wherein:
X is chosen from
a C5-8 cycloalkyl and cycloalkenyl optionally substituted with one to two oxo groups or one to three C1-4 alkyl, C1-4 alkoxy or C1-4 alkylamino chains each being branched or unbranched;
aryl, pyridinyl, pyrimidinyl, pyridinonyl, dihydropyridinonyl, maleimidyl, dihydromaleimidyl, piperdinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, nitro, nitrile, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is chosen from
a bond and
a C1-4 saturated or unsaturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N, or S(O)m and wherein Y is optionally independently substituted with one to two oxo groups, phenyl or one or more C1-4 alkyl optionally substituted by one or more halogen atoms;
Z is chosen from:
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, furanyl, thienyl, dihydrothiazolyl, dihydrothiazolyl sulfoxidyl, pyranyl, pyrrolidinyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino or CONH2;
tetrahydropyranyl, tetrahydrofuranyl, 1,3-dioxolanonyl, 1,3-dioxanonyl, 1,4-dioxanyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl, tetrahydropyrimidonyl, pentamethylene sulfidyl, pentamethylene sulfoxidyl, pentamethylene sulfonyl, tetramethylene sulfidyl, tetramethylene sulfoxidyl or tetramethylene sulfonyl which are optionally substituted with one to three nitrile, C1-3 alkyl, C1-3 alkoxy, hydroxy, amino, mono- or di-(C1-3 alkyl)amino or CONH2;
nitrile, C1-6 alkyl-S(O)m, halogen, hydroxy, C1-4 alkoxy, amino, mono- or di-(C1-6 alkyl)amino, mono- or di-(C1-3 alkyl)aminocarbonyl and NH2C(O).
In yet another embodiment of the invention there is provided a novel process of making compounds of the formula(I) as described immediately above and wherein:
X is chosen from
aryl, pyridinyl, pyrimidinyl, benzimidazole, 3H-imidazo[4,5-b]pyridine, piperazinyl, pyridazinyl and pyrazinyl; each being optionally independently substituted with one to three C1-4 alkyl, nitro, nitrile, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is chosen from
a bond and
a C1-4 saturated carbon chain wherein one of the carbon atoms is optionally replaced by O, N or S and wherein Y is optionally independently substituted with an oxo group;
Z is chosen from
phenyl, pyridinyl, pyrimidinyl, pyridazinyl, pyrazinyl, imidazolyl, dihydrothiazolyl, dihydrothiazolyl sulfoxide, pyranyl and pyrrolidinyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy;
tetrahydropyranyl, morpholinyl, thiomorpholinyl, thiomorpholinyl sulfoxidyl, piperidinyl, piperidinonyl, piperazinyl and tetrahydropyrimidonyl which are optionally substituted with one to two C1-2 alkyl or C1-2 alkoxy; and C1-3 alkoxy.
In yet still another embodiment of the invention there is provided a novel process of making compounds of the formula(I) as described immediately above and wherein:
X is chosen from
pyridinyl and pyrimidinyl, each being optionally independently substituted with one to three C1-4 alkyl, nitro, nitrile, mono- or di-(C1-3 alkyl)amino, mono- or di-(C1-3 alkylamino)carbonyl, NH2C(O), C1-6 alkyl-S(O)m or halogen;
Y is chosen from
a bond,
xe2x80x94CH2xe2x80x94, xe2x80x94CH2CH2xe2x80x94, xe2x80x94C(O)xe2x80x94, xe2x80x94Oxe2x80x94, xe2x80x94Sxe2x80x94, xe2x80x94NHxe2x80x94CH2CH2CH2xe2x80x94, xe2x80x94N(CH3)xe2x80x94 and xe2x80x94NHxe2x80x94;
In yet a further embodiment of the invention there is provided a novel process of making compounds of the formula(I) as described immediately above and wherein:
Y is chosen from
xe2x80x94CH2xe2x80x94, xe2x80x94NHxe2x80x94CH2CH2CH2xe2x80x94 and xe2x80x94NHxe2x80x94 and
Z is morpholinyl.
All terms as used herein in this specification, unless otherwise stated, shall be understood in their ordinary meaning as known in the art. For example, xe2x80x9cC1-6alkoxyxe2x80x9d is a C1-6alkyl with a terminal oxygen, such as methoxy, ethoxy, propoxy, pentoxy and hexoxy. All alkyl, alkenyl and alkynyl groups shall be understood as being branched or unbranched where structurally possible and unless otherwise specified. Other more specific definitions are as follows:
The term xe2x80x9caroylxe2x80x9d as used in the present specification shall be understood to mean xe2x80x9cbenzoylxe2x80x9d or xe2x80x9cnaphthoylxe2x80x9d.
The term xe2x80x9carylxe2x80x9d as used herein shall be understood to mean aromatic carbocycle or heteroaryl as defined herein.
The term xe2x80x9ccarbocyclexe2x80x9d shall be understood to mean an aliphatic hydrocarbon radical containing from three to twelve carbon atoms. Carbocycles include hydrocarbon rings containing from three to ten carbon atoms. These carbocycles may be either aromatic and non-aromatic ring systems. The non-aromatic ring systems may be mono- or polyunsaturated. Preferred carbocycles include but are not limited to cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl, cyclohexyl, cyclohexenyl, cycloheptanyl, cycloheptenyl, phenyl, indanyl, indenyl, benzocyclobutanyl, dihydronaphthyl, tetrahydronaphthyl, naphthyl, decahydronaphthyl, benzocycloheptanyl and benzocycloheptenyl. Certain terms for cycloalkyl such as cyclobutanyl and cyclobutyl shall be used interchangeably.
The term xe2x80x9cheterocyclexe2x80x9d, unless otherwise noted, refers to a stable nonaromatic 4-8 membered (but preferably, 5 or 6 membered) monocyclic or nonaromatic 8-11 membered bicyclic heterocycle radical which may be either saturated or unsaturated. Each heterocycle consists of carbon atoms and one or more, preferably from 1 to 4 heteroatoms selected from nitrogen, oxygen and sulfur. The heterocycle may be attached by any atom of the cycle, which results in the creation of a stable structure. Unless otherwise stated, heterocycles include but are not limited to, for example oxetanyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothiophenyl, piperidinyl, piperazinyl, morpholinyl, tetrahydropyranyl, dioxanyl, tetramethylene sulfonyl, tetramethylene sulfoxidyl, oxazolinyl, thiazolinyl, imidazolinyl, tertrahydropyridinyl, homopiperidinyl, pyrrolinyl, tetrahydropyrimidinyl, decahydroquinolinyl, decahydroisoquinolinyl, thiomorpholinyl, thiazolidinyl, dihydrooxazinyl, dihydropyranyl, oxocanyl, heptacanyl, thioxanyl, dithianyl or 2-oxa- or 2-thia-5-aza-bicyclo[2.2.1]heptanyl.
The term xe2x80x9cheteroarylxe2x80x9d, unless otherwise noted, shall be understood to mean an aromatic 5-8 membered monocyclic or 8-11 membered bicyclic ring containing 1-4 heteroatoms such as N, O and S. Unless otherwise stated, such heteroaryls include: pyridinyl, pyridonyl, quinolinyl, dihydroquinolinyl, tetrahydroquinoyl, isoquinolinyl, tetrahydroisoquinoyl, pyridazinyl, pyrimidinyl, pyrazinyl, benzimidazolyl, benzthiazolyl, benzoxazolyl, benzofuranyl, benzothiophenyl, benzpyrazolyl, dihydrobenzofuranyl, dihydrobenzothiophenyl, benzooxazolonyl, benzo[1,4]oxazin-3-onyl, benzodioxolyl, benzo[1,3]dioxol-2-onyl, tetrahydrobenzopyranyl, indolyl, indolinyl, indolonyl, indolinonyl, phthalimidyl.
Terms which are analogs of the above cyclic moieties such as aryloxy or heteroaryl amine shall be understood to mean an aryl, heteroaryl, heterocycle as defined above attached to it""s respective functional group.
As used herein, xe2x80x9cnitrogenxe2x80x9d and xe2x80x9csulfurxe2x80x9d include any oxidized form of nitrogen and sulfur and the quaternized form of any basic nitrogen.
The term xe2x80x9chalogenxe2x80x9d as used in the present specification shall be understood to mean bromine, chlorine, fluorine or iodine except as otherwise noted.
DDQxe2x80x942,3-Dichloro-5,6-dicyano-1,4-benzoquinone;
PPAxe2x80x94Polyphosphoric acid;
HOAcxe2x80x94acetic acid;
RT or rtxe2x80x94room temperature;
n-BuLixe2x80x94n-Butyllithium
DMExe2x80x941,2-Dimethoxyethane
DMSOxe2x80x94Methyl sulfoxide
DMFxe2x80x94N,N-Dimethylformamide
DBUxe2x80x941,8-Diazabicyclo[5.4.0]undec-7-ene
DMPUxe2x80x94N,Nxe2x80x2-Dimethylpropyleneurea
HMPAxe2x80x94Hexamethylphosphoramide
TEAxe2x80x94Triethylamine
THFxe2x80x94Tetrahydrofuran.
The compounds of the invention are only those which are contemplated to be xe2x80x98chemically stablexe2x80x99 as will be appreciated by those skilled in the art. For example, a compound which would have a xe2x80x98dangling valencyxe2x80x99, or a xe2x80x98carbanionxe2x80x99 are not compounds contemplated by the invention.
In order that this invention be more fully understood, the following examples are set forth in the overall reaction scheme below. These examples are for the purpose of illustrating preferred embodiments of this invention, and are not to be construed as limiting the scope of the invention in any way. Sample methods and starting materials to make compound (1) in Scheme I are shown in Examples 1 and 2 below.